The discovery of inhibitors of cyclin/cyclin dependent kinase (cdk) complexes is proposed which may have an antiprolifertive/antitumor effect of cells. Because overexpression of various cyclins have differential oncogenic potential, inhibitors will be assayed against a panel of cyclin/cdks. The goal of Phase I is to discover a compound which inhibits one or more cyclin/cdk complexes with a 10-fold improvement in inhibition relative to the most potent inhibitors known. Structure-activity studies will be pursued to optimize inhibition within a given cyclin/cdk complex. In Phase I of this proposal, 6 to 10 analogues each of known cdk inhibitors (olomucine, and flavopiridol) will be synthesized in parallel and screened. We will also prepare peptide fragments relating to known protein phosphorylation sites and measure their inhibition potentials. Inhibition specificity will be examined by screening against all cyclin/cdk complexes, as well as, other commercially available serine/threonine or tyrosine kinases. Compounds exhibiting sub-micromolar inhibition or kinase specificity will be evaluated for their cytotoxic/cytostatic potential, and their effect on cell cycle distribution. More advanced biochemical evaluation and in vivo studies of the drug candidates will be included in Phase II of this program.